ABSTRACT The type 2 diabetes mellitus (T2D) pandemic is a recognized re-emerging risk and challenge to tuberculosis (TB) control. However, strategies to identify and prevent the millions of T2D patients at risk of developing TB requires an understanding of the underlying mechanisms, which are poorly understood. Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that can replicate or get killed within macrophages (M?s). The ability of Mtb to survive within M?s depends largely on its ability to evade fusion of the Mtb-containing phagosomes with lysosomes or auto-phagosomes (autophagy pathway). However, in-vitro studies show that with appropriate M? activation (e.g. with IFN-?), intracellular Mtb is targeted to the phagolysosome or auto- phagolysosome for more effective killing, digestion and antigen presentation to T cells. Studies of human M? phenotype and function are often conceptualized through an M1 and M2 paradigm, with the M1 characterized by increased production of pro-inflammatory cytokines, while M2 having more immunosuppressive phenotype. We and others have used the M1/M2 paradigm to study TB pathogenesis, with M1 M?s exerting better Mtb killing when compared to the more permissive M2 (M1> M2). While the M1-M2 M? framework has been useful to study TB pathogenesis in-vitro, it does not capture the different environmental cues that influence M? plasticity in the T2D host. We address this gap by proposing the development of an in-vitro model to study TB pathogenesis in T2D patients using a recently described M? phenotype that is polarized to a ?metabolic? phenotype when cultured under conditions of high palmitate, glucose and insulin. We propose studies using this Metabolic M?s (Me) to determine how the altered metabolic environment in T2D patients affects the phenotype and functional responses of M?s to Mtb (vs M1 or M2). Our team is ideal conduct these studies: BIR (MPI) lives in the Texas-Mexico border where she has demonstrated high TB-T2D rates, and documented defects in monocytes and M?s from T2D patients. CJ (MPI) has 30+ yrs experience in M? responses to TB. Our consultants developed the Me M? model (LB), or have expertise in TB lung biology (JT). Our Aims are: Aim 1. Evaluate the response to Mtb by human Me M?s differentiated under controlled culture conditions that simulate T2D in the lungs. Aim 2. Identify differences in the Me M?s derived from monocytes of healthy vs T2D +/- TB patients. Our in-vitro TB-T2D M? model will retro-feed with in-vivo findings in T2D or TB-T2D patients or animal models, facilitating hypothesis generation and testing. Our access to monocytes from patients with TB or T2D will help identify the ?metabolic? or ?inflammatory? memories in vitro, that are retained after chronic exposure to altered metabolites in-vivo. Thus, our model will have an immediate impact for paving the design of effective host- directed therapies to polarize human diabetic M?s for optimal Mtb killing.